Studies on limb muscles have demonstrated that fatigue initiates an inhibitory reflex originating from the muscle which reduces the range of motoneuron firing rates that can be elicited by voluntary effort. Less direct evidence indicates this reflex operates also in fatigue of respiratory muscles. Reduced firing rates optimize force generation by minimizing fatigue onset at peripheral sites; thus fatigue is generally less evident during voluntary compared with stimulated contractions. For limb muscles this reflex prevents motoneuron firing rates exceeding those required for maximum motor unit tetanic activation, relation to muscle contractile slowing, without necessarily limiting force production. In contrast during diaphragmatic fatigue, twitch occlusion and EMG studies indicate that reduced motor drive is a major factor in the decline in voluntary force generating capacity. While the existence of a strong inhibitory reflex has been well demonstrated, it remains unclear whether this only involves spinal neural processes or requires higher brainstem involvement; or whether changes in intrinsic cortical and/or spinal neural excitability (central fatigue) also influence motoneuron firing rates. Changes in excitability of brainstem motor pathways will be assessed by cortical stimulation and by recording the incidence of F-waves elicited by stimulation of motor nerves. Mechanisms involved in fatigue-induced reflex inhibition will be examined. Motoneuron firing rates did not change when muscle speed was reduced by length changes or cooling. Thus metabolic causes are implied. In fatigue from non-ischemic low intensity intermittent contractions, no appreciable metabolic changes accompanied fatigue. Reflex inhibition will be tested under these conditions to compare with previous measurements made only during sustained MVCs in which large metabolic changes are seen. Similar tests will be performed during fatiguing contractions induced after either small and large diameter fibers have been blocked. The central distribution of inhibitory input within the spinal cord will be examined by recording maximum motoneuron firing rates from one muscle before and after an adjacent muscle has been fatigued. In each study the responses during ischemic sustained MVCs will be compared with those seen during intermittent low intensity exercise in which force is reduced by similar amounts, but more slowly under aerobic conditions.